Accumulation of beta-amyloid (A2) in brain extracellular fluids is the key event in the amyloid cascade leading to neuronal cell damage in the etiology of Alzheimer's disease (AD). Our preliminary data suggest that the choroid plexus sequesters A2 from the cerebrospinal fluid (CSF). The choroid plexus, as the tissue constituting the blood-CSF barrier, is also known to accumulate toxic metal lead (Pb) based on both human and animal studies. More recently, we found that acute in vivo Pb exposure increases A2 deposition in this tissue. Thus, this exploratory research proposal is designed to test the hypothesis that exposure to Pb results in an accumulation of beta-amyloids in the choroid plexus as well as in brain tissues;this may occur as a result of Pb alteration of beta-amyloid clearance by the choroid plexus by affecting beta-amyloid transport and/or enzymatic degradation in this tissue. Several techniques unique to the blood-brain barrier research such as in vitro two-chamber Transwell trans-epithelial model, in situ brain perfusion and in situ ventriculo-cisternal perfusion, along with transgenic mice that over-express A2, will be used to test the research hypothesis. The study proposed in this application will explore novel pathways of A2 clearance from brain extracellular fluids and will define the role of Pb exposure in these processes. Potential discovery of A2 transporters and metabolic regulatory mechanisms in the choroid plexus will help develop novel strategies for treatment and prevention of Alzheimer's disease. PUBLIC HEALTH RELEVANCE This study will explore novel pathways of A2 clearance from brain extracellular fluids and will define the role of Pb exposure in these processes. Results of this study will provide clues as to whether exposure to toxic metal lead (Pb) in the general population may contribute to the AD etiology. Potential discovery of A2 transporters and metabolic regulatory mechanism in the choroid plexus will help develop novel strategies for treatment and prevention of Alzheimer's disease.